4(phenyl-piperazinyl-methyl) benzamide derivatives and their use for the treatment of pain anxiety or gastrointestinal disorders

ABSTRACT

Compounds of general formula I R 1  is selected from any one of phenyl, pyridinyl, thienyl, furanyl, imidazolyl, pyrrolyl, triazolyl, thiazolyl, and pyridine N-oxide; R 2  is independently selected from ethyl and isopropyl; R 3  is independently selected from hydrogen and fluoro; R 4  is independently selected from —OH, —NH 2  and —NHSO 2 R 5 ; and R 5  is independently selected from hydrogen, —CF 3  and C 1 –C 6  alkyl, or salts thereof or separate enantiomers and salts thereof; where each R 1  heteroaromatic ring may optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched C 1 –C 6  alkyl, NO 2 , CF 3 , C 1 –C 6  alkoxy, chloro, fluoro, bromo, and iodo. The substitutions on the heteroaromatic ring may take place in any position on said ring systems; are disclosed and claimed in the present application, as well as separate enantiomers of the compounds and salts and pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain, anxiety and functional gastrointestinal disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Stage of International ApplicationNo. PCT/SE02/00956 that was filed on May 16, 2002. The InternationalApplication claims priority under 35 U.S.C. § 119(a) to SwedishApplication No. 0101772-2 filed May 18, 2001 and Swedish Application No.0103820-7 filed Nov. 15, 2001.

FIELD OF THE INVENTION

The present invention is directed to novel compounds, to a process fortheir preparation, their use and pharmaceutical compositions comprisingthe novel compounds. The novel compounds are useful in therapy, and inparticular for the treatment of pain, anxiety and functionalgastrointestinal disorders.

BACKGROUND OF THE INVENTION

The δ receptor has been identified as having a role in many bodilyfunctions such as circulatory and pain systems. Ligands for the δreceptor may therefore find potential use as analgesics, and/or asantihypertensive agents. Ligands for the δ receptor have also been shownto possess immunomodulatory activities.

The identification of at least three different populations of opioidreceptors (μ, δ and κ) is now well established and all three areapparent in both central and peripheral nervous systems of many speciesincluding man. Analgesia has been observed in various animal models whenone or more of these receptors has been activated.

With few exceptions, currently available selective opioid δ ligands arepeptidic in nature and are unsuitable for administration by systemicroutes. One example of a non-peptidic δ-agonist is SNC80 (Bilsky E. J.et al., Journal of Pharmacology and Experimental Therapeutics, 273(1),pp. 359–366 (1995)). There is however still a need for selectiveδ-agonists having not only improved selectivity, but also an improvedside-effect profile.

Thus, the problem underlying the present invention was to find newanalgesics having improved analgesic effects, but also with an improvedside-effect profile over current μ agonists, as well as having improvedsystemic efficacy.

Analgesics that have been identified and are existing in the prior arthave many disadvantages in that they suffer from poor pharmacokineticsand are not analgesic when administered by systemic routes. Also, it hasbeen documented that preferred δ agonist compounds, described within theprior art, show significant convulsive effects when administeredsystemically.

We have now found certain compounds that exhibit surprisingly improvedproperties, i.a. improved δ-agonist potency, in vivo potency,pharmacokinetic, bioavailability, in vitro stability and/or lowertoxicity.

OUTLINE OF THE INVENTION

The novel compounds according to the present invention are defined bythe formula I

wherein

-   R¹ is selected from any one of

wherein each R¹ heteroaromatic ring may optionally and independently befurther substituted by 1, 2 or 3 substituents selected from straight andbranched C₁–C₆ alkyl, halogenated C₁–C₆ alkyl, NO₂, CF₃, C₁–C₆ alkoxy,chloro, fluoro, bromo, and iodo;

-   R² is independently selected from ethyl and isopropyl;-   R³ is independently selected from hydrogen and fluoro;-   R⁴ is independently selected from —OH, —NH₂ and —NHSO₂R⁵; and-   R⁵ is independently selected from hydrogen, —CF₃ and C₁–C₆ alkyl,    provided that when R² is ethyl and R³ is hydrogen then R⁴ cannot be    —OH.

The substitutions on the heteroaromatic ring may take place in anyposition on said ring systems.

When the R¹ phenyl ring and the R¹ heteroaromatic ring(s) aresubstituted, the preferred substituents are selected from any one ofCF₃, methyl, iodo, bromo, fluoro and chloro, of which methyl is mostpreferred.

A further embodiment of the present invention is thus a compoundaccording to formula I wherein R¹ is as defined above and each R¹ phenylring and R¹ heteroaromatic ring may independently be further substitutedby a methyl group;

A further embodiment of the present invention is a compound according toFIG. 1 wherein R¹ is phenyl, pyrrolyl, furanyl, thienyl or imidazolyl;R² is ethyl or isopropyl; R³ is hydrogen or fluoro; R⁴ is —NH₂ or—NHSO₂R⁵; and R⁵ is C₁–C₆ alkyl, optionally with 1 or 2 of the preferredsubstituents on the R phenyl or R heteroaromatic ring.

An additional embodiment of the present invention is a compoundaccording to FIG. 1 wherein R¹ is phenyl, pyrrolyl, furanyl, thienyl orimidazolyl; R² is ethyl or isopropyl; R³ is hydrogen; R⁴ is —NHSO₂R⁵;and R⁵ is C₁–C₆ alkyl, optionally with 1 or 2 of the preferredsubstituents on the R¹ phenyl or R¹ heteroaromatic ring.

Other embodiments of the present invention are compounds according toFIG. 1 wherein a) R¹ is phenyl, pyrrolyl, or furanyl; R² is ethyl orisopropyl; R³ is hydrogen or fluoro; and R⁴ is —NH₂; b) R¹ is thienyl orimidazolyl; R² is ethyl or isopropyl; R³ is hydrogen or fluoro; and R⁴is —NH₂; c) R¹ is phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; R²is ethyl or isopropyl; R³ is hydrogen or fluoro; R⁴ is —NHSO₂R⁵; and R⁵is C₁–C₆ alkyl; and d) R¹ is phenyl, pyrrolyl, furanyl, thienyl orimidazolyl; R² is ethyl or isopropyl; R³ is hydrogen or fluoro; R⁴ is—NHSO₂R⁵; and R⁵ is C₁–C₆ alkyl, wherein all embodiments a) to d) mayoptionally be substituted with 1 or 2 of the preferred substituents onthe R¹ phenyl or R¹ heteroaromatic ring.

Within the scope of the invention are also separate enantiomers andsalts of the compounds of the formula I, including salts of enantiomers.Also within the scope of the present invention are mixtures of theseparate enantiomers, such as the racemic mixuture, as well as salts ofmixtures of separate enantiomers.

Separation of racemic mixtures into separate enantiomers is well knownin the art and may be accomplished for example by separation on asuitable chiral chromatography column. Preparation of salts is wellknown in the art, and may be accomplished for example by mixing acompound of formula I in a suitable solvent with the desired protic acidand isolation by means standard in the art. Salts of compounds offormula I include pharmaceutically acceptable salts and alsopharmaceutically unacceptable salts.

The novel compounds of the present invention are useful in therapy,especially for the treatment of various pain conditions such as chronicpain, neuropathic pain, acute pain, cancer pain, pain caused byrheumatoid arthritis, migraine, visceral pain etc. This list shouldhowever not be interpreted as exhaustive.

Compounds of the invention are useful as immunomodulators, especiallyfor autoimmune diseases, such as arthritis, for skin grafts, organtransplants and similar surgical needs, for collagen diseases, variousallergies, for use as anti-tumour agents and anti viral agents.

Compounds of the invention are useful in disease states wheredegeneration or dysfunction of opioid receptors is present or implicatedin that paradigm. This may involve the use of isotopically labelledversions of the compounds of the invention in diagnostic techniques andimaging applications such as positron emission tomography (PET).

Compounds of the invention are useful for the treatment of diarrhoea,depression, anxiety and stress-related disorders such as post-traumaticstress disorders, panic disorder, generalized anxiety disorder, socialphobia, and obesessive compulsive disorder; urinary incontinence,various mental illnesses, cough, lung oedema, various gastro-intestinaldisorders, e.g. constipation, functional gastrointestinal disorders suchas Irritable Bowel Syndrome and Functional Dyspepsia, Parkinson'sdisease and other motor disorders, traumatic brain injury, stroke,cardioprotection following miocardial infarction, spinal injury and drugaddiction, including the treatment of alcohol, nicotine, opioid andother drug abuse and for disorders of the sympathetic nervous system forexample hypertension.

Compounds of the invention are useful as an analgesic agent for useduring general anaesthesia and monitored anaesthesia care. Combinationsof agents with different properties are often used to achieve a balanceof effects needed to maintain the anaesthetic state (e.g. amnesia,analgesia, muscle relaxation and sedation). Included in this combinationare inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockersand opioids.

Also within the scope of the invention is the use of any of thecompounds according to the formula I above, for the manufacture of amedicament for the treatment of any of the conditions discussed above.

A further aspect of the invention is a method for the treatment of asubject suffering from any of the conditions discussed above, whereby aneffective amount of a compound according to the formula I above, isadministered to a patient in need of such treatment.

Methods of Preparation

The compounds of the present invention can be prepared using thefollowing general procedure.

Preparation of Phenols EXAMPLES 1–3

The compounds of formula I wherein R⁴ is —OH is prepared by reacting acompound of the general formula II

wherein R² and R³ are as defined in FIG. 1 and R⁴ is OMe, withBoc-piperazine in acetonitrile in the presence of triethylamine understandard conditions, followed by removal of the Boc protection groupunder standard conditions to give a compound of the Formula III

which is thereafter alkylated under reductive conditions with a compoundof the Formula R¹—CHO, followed by cleavage of the methyl ether usingBBr₃ in dichloromethane to give a compound of the Formula I wherein R⁴is —OH.

Preparation of Anilines EXAMPLES 4–6

The compound of formula I wherein R⁴ is —NH₂ is prepared by reacting acompound of the general formula IV

wherein R² and R³ are as defined in FIG. 1 and R⁴ is NO₂, withBoc-piperazine in acetonitrile in the presence of triethylamine understandard conditions, followed by removal of the Boc protection groupunder standard conditions to give a compound of the Formula V

which is thereafter alkylated under reductive conditions with a compoundof the Formula R¹—CHO, followed by reduction of the nitro group usinghydrogen and palladium on charcoal to give a compound of the Formula Iwherein R⁴ is —NH₂.

Preparation of Methyl Sulfonanilides EXAMPLES 7–8

The compound of formula I wherein R⁴ is —NHSO₂R⁵ is prepared by reactinga compound of the general formula VI

wherein R² and R³ are as defined in claim 1 and R⁴ is NO₂, withBoc-piperazine in acetonitrile in the presence of triethylamine understandard conditions, followed reduction of the nitro group byhydrogenolysis using palladium on charcoal as the catalyst,metanesulphonylation using methanesulphonylanhydride in dichloromethanein the presence of triethylamine, and thereafter removal of the Bocprotection group under standard conditions to give a compound of theFormula VII

which is thereafter alkylated under reductive conditions with a compoundof the Formula R¹—CHO, followed by reduction of the nitro group usinghydrogen and palladium on charcoal to give a compound of the Formula Iwherein R⁴ is —NHSO₂R⁵.

Within the scope of the invention are also separate enantiomers andsalts of the compounds of the Formula I, including salts of enantiomers.Compounds of Formula I are chiral compounds, with thediarylmethylpiperazine group being the stereogenic center, see FIG. 1 *below.

A further embodiment of the present invention is thus the (−)-enantiomerof a compound according to Formula I, as well as a salt of saidcompound.

A further embodiment of the present invention is thus the (+)-enantiomerof a compound according to Formula I, as well as a salt of saidcompound.

EXAMPLES

The invention will now be described in more detail by the followingExamples, which are not to be construed as limiting the invention.

Intermediate 14-[(4-fluoro-3-methoxyphenyl)hydroxy)methyl]-N,N-diisopropyl-benzamide

N,N-Diisopropyl-4-iodobenzamide (6.0 g, 18 mmol) was dissolved in THF(200 mL) and cooled to −78° C. under nitrogen atmosphere. n-BuLi (14 mL,1.3 M solution in hexane, 18 mmol) was added dropwise during 10 min at−65 to −78° C. 4-fluoro-3-methoxybenzaldehyde (2.8 g, 18 mmol) was addeddropwise dissolved in THF (5 mL). NH₄Cl (aq.) was added after 30 min.After concentration in vacuo, extraction with EtOAc/water, drying(MgSO₄) and evaporation of the organic phase, the residue was purifiedby chromatography on silica (0–75% EtOAc/heptane) to yield the desiredproduct (3.9 g, 60%). ¹H NMR (CDCl₃) δ 1.0–1.6 (m, 12H), 2.65 (d, J=4Hz, 1H), 3.4–3.9 (m, 2H), 3.80 (s, 3H), 6.10 (d, J=4 Hz, 1H), 6.76 (m,1H), 6.95 (m, 1H), 7.04 (m, 1H), 6.76 (m, 1H), 7.25, 7.40 (2d, J=7.5 Hz,4H).

Intermediate 24-[(4-fluoro-3-methoxyphenyl)(1-piperazinyl)methyl]-N,N-diisopropylbenzamide

Intermediate 1 (3.9 g, 11 mmol) was dissolved in dry CH₂Cl₂ (50 mL) andtreated with SOBr₂ (0.88 mL, 11 mmol) at 0 to 25° C. for 30 min.Neutralization with KHCO₄ (aq.) and drying (K₂CO₄) of the organic phasewas followed by solvent evaporation in vacuo. The residue and Et₃N (1.8mL, 13 mmol) was dissolved in MeCN (50 mL) and stirred withBoc-piperazine (2.1 g, 11 mmol) at 25° C. for 12 h. Concentration invacuo and chromatography on silica (0 to 50% EtOAc in heptane) gave 4.6g. 1.6 g was treated with TFA in CH₂Cl₂ (1:1), concentrated in vacuo,extracted CH₂Cl₂/K₂CO₄ (aq.), dried (K₂CO₄) and evaporated in vacuo togive Intermediate 2 (1.3 g, 81% from intermediate 1). MS (ES) 428.21(MH+).

Example 14-[1-(4-Benzyl-piperazin-1-yl)-1-(4-fluoro-3-hydroxy-phenyl)-methyl]-N,N-diisopropyl-benzamide

Intermediate 2 (0.41 g, 0.96 mmol) and triethylamine (0.20 mL, 1.4 mmol)were dissolved in MeCN (10 mL). Benzyl bromide (0.14 mL, 1.1 mmol) wasadded with stirring at 25° C. After 12 h the solution was concentratedand purified by reverse phase chromatography (LiChroprep RP-18, 10–80%MeCN in water, 0.1% TFA). 0.53 g of free base was obtained afterextraction with CH₂Cl₂/K₂CO₄ (aq.), drying (K₂CO₄) and evaporation invacuo. Treatment with boron tribromide (4 eq., 1M solution in CH₂Cl₂) inCH₂Cl₂ at −78° C., addition of water, concentration in vacuo and reversephase chromatography gave Example 1 as the trifluoroacetate (0.35 g,50%). MS (ES) 504.22 (MH+). IR (NaCl) 3222, 1677, 1592, 1454, 1346,1201, 1135 (cm-1). ¹H NMR (CD₃OD) δ=1.1, 1.5 (m, 12H), 2.3 (m, 3H),2.9–3.8 (m, 7H), 4.33 (s, 2H), 4.75 (s, 1H), 6.60 (m, 1H), 6.83 (m, 1H),6.94 (m, 1H), 7.24 (d, J=8 Hz, 2H), 7.47 (m, 7H). Anal. Calc. forC₃₁H₃₈FN₃O₂×0.8C₄H₂F₆O₄ C:59.87, H:5.82, N:6.12. Found C:60.06, H:5.83,N:6.19.

Example 24-[1-(4-Fluoro-3-hydroxy-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin-1-yl)-methyl]-N,N-diisopropyl-benzamide

Intermediate 2 (0.43 g, 1.0 mmol) was dissolved in MeOH (5 mL) with3-thiophene-carboxaldehyde (0.11 mL, 1.2 mmol) and HOAc (57 μL, 1.0mmol) and stirred for 1 h. Sodium cyanoborohydride (63 mg, 1.0 mmol) wasadded in portions over 6 h and the reaction was stirred at 25° C. for anadditional 12 h before working up by concentration in vacuo andextraction (CH₂C₂/K₂CO₃(aq)). Purification by reverse phasechromatography as for Example 1 to give 0.32 g (0.62 mmol) as free base.Treatment with boron tribromide as for Example 1 and chromatography gaveExample 2 (0.20 g, 26%) as the trifluoroacetate. MS (ES) 510.17 (MH+).IR (NaCl) 3281, 1674, 1606, 1454, 1346, 1200, 1135 (cm-1). ¹H NMR(CD₃OD) δ=1.1, 1.5 (m, 12H), 2.30 (m, 2H), 2.9–3.7 (m, 10H), 4.37 (s,2H), 4.75 (s, 1H), 6.60 (m, 1H), 6.84 (m, 1H), 6.94 (m, 1H), 7.18 (m,1H), 7.25, 7.48 (2d, J=8.0 Hz, 4H), 7.55 (m, 1H), 7.65 (m, 1H). Anal.Calc. for C₂₉H₃₆FN₃O₂S×0.8 C₄H₂F₆O₄×0.5 H₂O, C:55.16, H:5.55, N:5.99.Found, C:55.12, H:5.39, N:6.07.

Example 34-{1-(4-Fluoro-3-hydroxy-phenyl)-1-[4-(1H-imidazol-2-ylmethyl)-piperazin-1-yl]-methyl}-N,N-diisopropyl-benzamide

Employing the same procedure as for Example 2 reaction with2-imidazole-carboxaldehyde (0.10 g, 1.11 mmol) followed by treatmentwith boron tribromide (6 eq.) gave Example 3 (0.18 g, 25%) as thetrifluoroacetate. MS (ES) 494.23 (MH+). IR (NaCl) 3123, 1673, 1592,1454, 1350, 1201, 1135 (cm-1). ¹H NMR (CD₃OD) δ=1.1, 1.5 (m, 12H),2.7–3.8 (m, 10H), 3.95 (s, 2H), 5.20 (m, 1H), 6.70 (m, 1H), 6.94 (m,1H), 7.02 (m, 1H), 7.32, 7.58 (2d, J=8.0 Hz, 4H), 7.46 (s, 1H). Anal.Calc. for C₂₈H₃₆FN₅O₂×1.2 C₄H₂F₆O₄×0.7 H₂O, C:50.51, H:5.14, N:8.98.Found, C:50.44, H:5.18, N:9.11.

Intermediate 3 4-[hydroxy(3-nitrophenyl)methyl]-N,N-diisopropylbenzamide

Procedure as for intermediate 1 but after addition of n-BuLi thesolution was cannulated into a solution of 3-nitrobenzaldehyde (2.7 g,18 mmol) in toluene/THF (approx. 1:1, 100 mL) at −78° C. Workup andchromatography gave for intermediate 3 (2.4 g, 37%). ¹H NMR (CDCl₃) δ1.1–1.7 (m, 12H), 3.90 (d, J=3.5 Hz, 1H), 3.4–3.9 (m, 2H), 5.91 (s,J=3.5 Hz, 1H), 7.27, 7.35 (2d, J=8 Hz, 4H), 7.51 (m, 1H), 7.71 (m, 1H),8.13 (m, 1H), 8.30 (s, 1H).

Intermediate 4N,N-diisopropyl-4-[(3-nitrophenyl)(1-piperazinyl)methyl]benzamide

Employing the same procedure as for intermediate 2, intermediate 3(2.4g, 6.7 mmol) gave Boc-protected intermediate 4 (2.83 g, 81%). TFAtreatment quantitatively gave intermediate 4, MS (ES) 425.23 (MH+).

Example 44-[1-(3-Amino-phenyl)-1-(4-benzyl-piperazin-1-yl)-methyl]-N,N-diisopropyl-benzamide

Reaction of 7 (0.40 g, 0.94 mmol) with benzyl bromide as for Example 1was followed by hydrogenation (H₂, 40 psi) with 10% Pd/C (50 mg) in EtOH(25 mL) and 2 N HCl (1.2 mL, 2.4 mmol) for 2 h. Purification by reversephase chromatography using the same conditions as for Example 1 gaveExample 4 (0.20 g, 30%) as the trifluoroacetate. MS (ES) 485.40 (MH+).IR (NaCl) 3414, 1673, 1605, 1455, 1345, 1201, 1134 (cm-1). ¹H NMR(CD₃OD) δ=1.1, 1.5 (m, 12H), 2.3 (m, 2H), 2.9–3.8 (m, 8H), 4.31 (s, 2H),4.47 (s, 1H), 7.02 (m, 1H), 7.21–7.52 (m, 12H). Anal. Calc. forC₃₁H₄₀N₄O×1.2 C₄H₂F₆O₄×0.5 H₂O, C:56.04, H:5.70, N:7.30. Found, C:56.06,H:5.67, N:7.41.

Example 54-[1-(3-Amino-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin-1-yl)-methyl]-N,N-diisopropyl-benzamide

Reaction of intermediate 4 (0.40 g, 0.94 mmol) with3-thiophene-carboxaldehyde as for example 2 was followed byhydrogenation (H₂, 30 psi) with 10% Pd/C (50 mg) in EtOH (25 mL) and 2 NHCl (1.0 mL, 2.0 mmol) for 12 h. Purification by reverse phasechromatography using the same conditions as for Example 1 gave Example 5(0.13 g, 20%) as the ditrifluoroacetate. MS (ES) 491.28 (MH+). IR (NaCl)3408, 1673, 1605, 1455, 1345, 1201, 1134 (cm-1). ¹H NMR (CD₃OD) δ=1.1,1.5 (m, 12H), 2.3 (m, 2H), 2.9–3.8 (m, 8H), 4.35 (s, 2H), 4.44 (s, 1H),6.98 (m, 11), 7.167.32 (m, 6H), 7.49 (d, J=8 Hz, 2H), 7.55 (m, 1H), 7.64(m, 1H). Anal. Calc. for C₂₉H₃₈N₄OS×1.3 C₄H₂F₆O₄×0.6 H₂O, C:51.48,H:5.28, N:7.02. Found, C:51.51, H:5.20, N:7.01.

Example 64-{1-(3-Amino-phenyl)-1-[4-(1H-imidazol-2-ylmethyl)-piperazin-1-yl]-methyl}-N,N-diisopropyl-benzamide

Employing the same procedure as for Example 2, reaction of intermediate4 with 2-imidazole-carboxaldehyde (0.10 g, 1.1 mmol) followed byhydrogenation gave Example 6 (45 mg, 7%) as ditrifluoroacetate salt.MS(ES) 475.30 (MH+). IR (2×TFA, NaCl) 3351, 1674, 1621, 1455, 1349,1202, 1134 (cm-1). ¹H NMR (2×TFA, CD₃OD) δ=1.1, 1.5 (m, 12H), 2.9–3.8(m, 8H), 4.35 (s, 2H), 4.44 (s, 1H), 6.98 (m, 1H), 7.16–7.32 (m, 6H),7.49 (d, J=8 Hz, 2H), 7.55 (m, 1H), 7.64 (m, 1H). Anal. Calc. forC₂₈H₃₈N₆O×1.6 C₄H₂F₆O₄×0.8 H₂O, C:48.39, H:5.05, N:9.84. Found, C:48.43,H:5.06, N:9.85.

Intermediate 5N,N-diisopropyl-4-[{3-[(methylsulfonyl)amino]phenyl}(1-piperazinyl)methyl]benzamide

Intermediate 3 gave Boc-protected Intermediate 4 as described forIntermediate 4, above. Boc-protected Intermediate 4 (1.21 g, 2.3 mmol)was hydrogenated under H₂ at 30 psi with 10% Pd/C (150 mg) in AcOH (25mL) for 12 h. Evaporation in vacuo and extraction with CH₂Cl₂/K₂CO₄(aq.) gave 1.1 g (2.3 mmol) of the intermediate aniline, which wasdissolved in MeCN/CH₂Cl₂ (1:1, 10 mL). Et₃N (0.48 mL, 3.4 mmol), thenmethanesulponylanhydride (0.41 g, 2.4 mmol) was added at 0° C. Afterwarming to room temperature the reaction was worked up by extractionCH₂Cl₂/brine. Purification by chromatography on silica (0–5%MeOH/CH₂Cl₂) gave Boc-protected Intermediate 5 (1.3 g, 97%). Treatmentwith TFA in CH₂Cl₂ quantitatively gave Intermediate 5. MS (ES) 473.16(MH+).

Example 7N,N-Diisopropyl-4-[1-(3-methanesulfonylamino-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin-1-yl)-methyl]-benzamide

Reductive amination procedure as for Example 2. Intermediate 5 (0.20 g,0.43 mmol) gave Example 7 (90 mg, 26%) as ditrifluoroacetate salt. Thedihydrochloride salt was obtained after extraction of the free base withCH₂Cl₂/K₂CO₄ (aq.) and treatment with 2 eq. HCl (aq.). MS (ES) 569.21(MH+). IR (free base, NaCl) 1604, 1455, 1340, 1151 (cm-1). ¹H NMR (freebase, CDCl₃) δ=0.9–1.7 (m, 12H), 2.5 (m, 8H), 2.85 (s, 3H), 3.55 (s,2H), 3.8 (m, 2H), 4.22 (s, 1H), 7.00–7.40 (m, 12H). Anal. Calc. forC₃₀H₄₀N₄O₃S₂×2.6 HCl, C:54.30, H:6.47, N:8.44. Found, C:54.33, H:6.20,N:8.32.

Example 84-([4-(3-furylmethyl)-1-piperazimyl]{3-[(methylsulfonyl)amino]phenyl}-N,N-diisopropyl-benzamide

Employing the same procedure as for Intermediate 7. Intermediate 5 (0.21g, 0.45 mmol) gave Example 8 (80 mg, 32%) as free base. MS (ES) 553.23(MH+). IR (free base, NaCl) 1604, 1455, 1340, 1151 (cm-1). ¹H NMR (freebase, CDCl₃) δ=1.0–2.6(m, 20H), 2.91 (s, 3H), 3.40 (s, 2H), 4.22 (s,1H), 6.39 (s, 1H), 7.06–7.42 (m, 11H). Anal. Calc. for C₃₀H₄₀N₄O₄S×2.8HCl, C:55.03, H:6.59, N:8.56. Found, C:54.93, H:5.93, N:8.49.

Example 94-{(3-aminophenyl)[4-(3-thienylmethyl)-1-piperazinyl]methyl}-N,N-diethylbenzamide

N,N-diethyl-4-[(3-nitrophenyl)(1-piperazinyl)methyl]benzamide (preparedanalogous to intermediate (4) in Scheme 2) (0.85 g, 2.1 mmol) wasdissolved in MeOH (5 mL) with 3-thiophenecarboxaldehyde (0.40 mL, 4.3mmol) and HOAc (60 μL, 1.0 mmol) and stirred for 1 h. Sodiumcyanoborohydride (135 mg, 2.1 mmol) was added in portions over 6 h andthe reaction was stirred at 25° C. for an additional 12 h before workingup by concentration in vacuo and extraction (CH₂Cl₂/K₂CO₃(aq)).Purification by chromatography on silica gave the 3-thienylmethylderivative (0.45 g, 43%). Hydrogenation of the product (0.30 g, 0.61mmol) and reverse phase chromatography gave the title compound (0.17 g,35%) as the tris-trifluoroacetate. MS (ES) 463.34 (MH+). IR (NaCl) 3418,1673, 1600, 1461, 1200, 1135 (cm-1). ¹H NMR (CD₃OD) δ=1.17, 1.31 (m,6H), 2.45 (m, 2H), 3.11 (m, 2H), 3.24–3.66 (m, 10H), 4.47 (s, 2H), 4.62(s, 1H), 7.21 (m, 1H), 7.31 (m, 1H), 7.39–7.56 (m, 5H), 7.61–7.68 (m,3H), 7.77 (m, 1H).

Example 104-[(3-aminophenyl)(4-benzyl-1-piperazinyl)methyl]-N,N-diethylbenzamide

N,N-diethyl-4-[(3-nitrophenyl)(1-piperazinyl)methyl]benzamide (1.7 g g,4.3 mmol) and triethylamine (1.2 mL, 8.6 mmol) was dissolved in MeCN (10mL). Benzyl bromide (0.56 mL, 4.7 mmol) was added with stirring at 25°C. After 12 h the solution was concentrated in vacuo. Extraction(CH₂Cl₂/K₂CO₃(aq)) and purification by chromatograpy on silica gave thebenzylated product (1.4 g, 2.9 mmol). Hydrogenation (H₂, 40 psi) with10% Pd/C (100 mg) in EtOH (25 mL) and 2 N HCl (2.5 mL, 5 mmol) for 4 hwas followed by concentration in vacuo and reverse phase chromatographyto give the title compound as the tris-trifluoroacetate (0.9 g, 26%). MS(ES) 457.26 (MH+). IR (NaCl) 3422, 1672, 1603, 1458, 1209, 1133 (cm-1).¹H NMR (CD₃OD) δ=1.1, 1.2 (m, 6H), 2.3 (m, 2H), 2.9–3.6 (m, 10H), 4.33(s, 2H), 4.49 (s, 1H), 5.48 (s, 2H), 7.01 (m, 1H), 7.24–7.34 (m, 5H),7.47 (m, 5H), 7.52 (d, J=7.5 Hz, 2H).

Example 114-((4-benzyl-1-piperazinyl){3-[(methylsulfonyl)amino]phenyl}methyl)-N,N-diethylbenzamide

The product of Example 10 (0.35 g, 0.76 mmol) and triethylamine (0.12mL, 0.84 mmol) was dissolved in MeCN (10 mL) and methanesulfonicanhydride (0.14 g, 0.84 mmol) was added at 0° C. After stirring 10 minat 25° C., the solution was concentrated in vacuo and purified byreverse phase chromatography to give the title compound as thebis-trifluoroacetate (0.23 g, 40%). MS (ES) 535.21 (MH+). IR (NaCl)3479, 1673, 1604, 1458, 1337, 1200, 1150 (cm-1). ¹H NMR (CD₃OD) δ=1.18,1.31 (m, 6H), 2.41 (m, 2H), 2.98 (s, 3H), 3.13 (m, 21), 3.28–3.65 (m,8H), 4.44 (s, 2H), 4.57 (s, 1H), 5.57 (d, J=2 Hz, 2H), 7.15 (m, 1H),7.30 (m, 1H), 7.37 (m, 1H), 7.42 (m, 2H), 7.54–7.60 (m, 6H), 7.63 (m,2H).

Pharmaceutical Compositions

The novel compounds according to the present invention may beadministered orally, intramuscularly, subcutaneously, topically,intranasally, intraperitoneally, intrathoracially, intravenously,epidurally, intrathecally, intracerebroventricularly and by injectioninto the joints.

A preferred route of administration is orally, intravenously orintramuscularly.

The dosage will depend on the route of administration, the severity ofthe disease, age and weight of the patient and other factors normallyconsidered by the attending physician, when determining the individualregimen and dosage level as the most appropriate for a particularpatient.

For preparing pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

For preparing suppository compositions, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmolds and allowed to cool and solidify.

Suitable carriers are magnesium carbonate, magnesium stearate, talc,lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and thelike.

Salts include, but are not limited to pharmaceutically acceptable salts.Examples of pharmaceutically acceptable salts within the scope of thepresent invention include: acetate, benzenesulfonate, benzoate,bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate,chloride, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, glucaptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, isethionate, lactate, lactobionate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, pamoate (embonate),pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate,triethiodide, benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminium, calcium, lithium,magnesium, potassium, sodium, and zinc. Examples of pharmaceuticallyunacceptable salts within the scope of the present invention include:hydroiodide, perchlorate, and tetrafluoroborate. Pharmaceuticallyunacceptable salts could be of use because of their advantageousphysical and/or chemical properties, such as crystallinity.

Preferred pharmaceutically acceptable salts are the hydrochlorides,sulfates and bitartrates. The hydrochloride and sulfate salts areparticularly preferred.

The term composition is intended to include the formulation of theactive component with encapsulating material as a carrier providing acapsule in which the active component (with or without other carriers)is surrounded by a carrier which is thus in association with it.Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be used as solid dosageforms suitable for oral administration.

Liquid from compositions include solutions, suspensions, and emulsions.Sterile water or water-propylene glycol solutions of the activecompounds may be mentioned as an example of liquid preparations suitablefor parenteral administration. Liquid compositions can also beformulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolvingthe active component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

Preferably the pharmaceutical compositions is in unit dosage form. Insuch form, the composition is divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofthe preparations, for example, packeted tablets, capsules, and powdersin vials or ampoules. The unit dosage form can also be a capsule,cachet, or tablet itself, or it can be the appropriate number of any ofthese packaged forms.

Biological Evaluation

In vitro Model

Cell Culture

-   -   A. Human 293S cells expressing cloned human μ, δ, and κ        receptors and neomycin resistance were grown in suspension at        37° C. and 5% CO₂ in shaker flasks containing calcium-free        DMEM10% FBS, 5% BCS, 0.1% Pluronic F-68, and 600 μg/ml        geneticin.    -   B. Mouse and rat brains were weighed and rinsed in ice-cold PBS        (containing 2.5 mM EDTA, pH 7.4). The brains were homogenized        with a polytron for 15 sec (mouse) or 30 sec (rat) in ice-cold        lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTA, with        phenylmethylsulfonyl fluoride added just prior use to 0.5 MmM        from a 0.5M stock in DMSO:ethanol).        Membrane Preparation

Cells were pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0,2.5 mM EDTA, with PMSF added just prior, to use to 0.1 mM from a 0.1 mMstock in ethanol), incubated on ice for 15 min, then homogenized with apolytron for 30 sec. The suspension was spun at 1000 g (max) for 10 minat 4° C. The supernatant was saved on ice and the pellets resuspendedand spun as before. The supernatants from both spins were combined andspun at 46,000 g (max) for 30 min. The pellets were resuspended in coldTris buffer (50 mM Tris/Cl, pH 7.0) and spun again. The final pelletswere resuspended in membrane buffer (50 mM Tris, 0.32 M sucrose, pH7.0). Aliquots (1 ml) in polypropylene tubes were frozen in dryice/ethanol and stored at −70° C. until use. The protein concentrationswere determined by a modified Lowry assay with sodium dodecyl sulfate.

Binding Assays

Membranes were thawed at 37° C., cooled on ice, passed 3 times through a25-gauge needle, and diluted into binding buffer (50 mM Tris, 3 mMMgCl₂, 1 mg/ml BSA (Sigma A-7888), pH 7.4, which was stored at 4° C.after filtration through a 0.22 m filter, and to which had been freshlyadded 5 μg/ml aprotinin, 10 μM bestatin, 10 μM diprotin A, no DTT).Aliquots of 100 μl were added to iced 12×75 mm polypropylene tubescontaining 100 μl of the appropriate radioligand and 100 μl of testcompound at various concentrations. Total (TB) and nonspecific (NS)binding were determined in the absence and presence of 10 μM naloxonerespectively. The tubes were vortexed and incubated at 25° C. for 60–75min, after which time the contents are rapidly vacuum-filtered andwashed with about 12 ml/tube iced wash buffer (50 mM Tris, pH 7.0, 3 mMMgCl₂) through GF/B filters (Whatman) presoaked for at least 2 h in 0.1%polyethyleneimine. The radioactivity (dpm) retained on the filters wasmeasured with a beta counter after soaking the filters for at least 12 hin minivials containing 6–7 ml scintillation fluid. If the assay is setup in 96-place deep well plates, the filtration is over 96-placePEI-soaked unifilters, which were washed with 3×1 ml wash buffer, anddried in an oven at 55° C. for 2 h. The filter plates were counted in aTopCount (Packard) after adding 50 μl MS-20 scintillation fluid/well.

Functional Assays

The agonist activity of the compounds is measured by determining thedegree to which the compounds receptor complex activates the binding ofGTP to G-proteins to which the receptors are coupled. In the GTP bindingassay, GTP[γ]³⁵S is combined with test compounds and membranes fromHEK-293S cells expressing the cloned human opioid receptors or fromhomogenised rat and mouse brain. Agonists stimulate GTP[γ]³⁵S binding inthese membranes. The EC₅₀ and E_(max) values of compounds are determinedfrom dose-response curves. Right shifts of the dose response curve bythe delta antagonist naltrindole are performed to verify that agonistactivity is mediated through delta receptors.

Procedure for Rat Brain GTP

Rat brain membranes are thawed at 37° C., passed 3 times through a25-gauge blunt-end needle and diluted in the GTPγS binding (50 mM Hepes,20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl₂, pH 7.4, Add fresh: 1 mMDTT, 0.1% BSA). 120 μM GDP final is added membranes dilutions. The EC50and Emax of compounds are evaluated from 10-point dose-response curvesdone in 300 μl with the appropriate amount of membrane protein (20μg/well) and 100000–130000 dpm of GTPγ³⁵S per well (0.11–0.14 nM). Thebasal and maximal stimulated binding are determined in absence andpresence of 3 μM SNC-80

Data Analysis

The specific binding (SB) was calculated as TB-NS, and the SB in thepresence of various test compounds was expressed as percentage ofcontrol SB. Values of IC₅₀ and Hill coefficient (n_(H)) for ligands indisplacing specifically bound radioligand were calculated from logitplots or curve fitting programs such as Ligand, GraphPad Prism,SigmaPlot, or ReceptorFit. Values of K_(i) were calculated from theCheng-Prussoff equation. Mean ±S.E.M. values of IC₅₀, K_(i) and n_(H)were reported for ligands tested in at least three displacement curves.Biological activity of the compounds of the present invention isindicated in Table 2.

TABLE 2 Biological data. HDELTA RAT BRAIN MOUSE BRAIN Ex. (nM) (nM) (nM)# IC₅₀ EC₅₀ % EMax EC₅₀ % EMax EC₅₀ % EMax 1– 0.50– 0.32– 94– 2.9– 125–4.9– 126– 11 13 104 106 867 159 1441 154

Receptor Saturation Experiments

Radioligand K_(δ) values were determined by performing the bindingassays on cell membranes with the appropriate radioligands atconcentrations ranging from 0.2 to 5 times the estimated K_(δ) (up to 10times if amounts of radioligand required are feasible). The specificradioligand binding was expressed as pmole/mg membrane protein. Valuesof K_(δ) and B_(max) from individual experiments were obtained fromnonlinear fits of specifically bound (B) vs. nM free (F) radioligandfrom individual according to a one-site model.

Determination of Mechano-Allodynia Using Von Frey Testing

Testing was performed between 08:00 and 16:00 h using the methoddescribed by Chaplan et is al. (1994). Rats were placed in Plexiglascages on top of a wire mesh bottom which allowed access to the paw, andwere left to habituate for 10–15 min. The area tested was themid-plantar left hind paw, avoiding the less sensitive foot pads. Thepaw was touched with a series of 8 Von Frey hairs with logarithmicallyincremental stiffness (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51, and15.14 grams; Stoelting, Ill., USA). The von Frey hair was applied fromunderneath the mesh floor perpendicular to the plantar surface withsufficient force to cause a slight buckling against the paw, and heldfor approximately 6–8 seconds. A positive response was noted if the pawwas sharply withdrawn. Flinching immediately upon removal of the hairwas also considered a positive response. Ambulation was considered anambiguous response, and in such cases the stimulus was repeated.

Testing Protocol

The animals were tested on postoperative day 1 for the FCA-treatedgroup. The 50% withdrawal threshold was determined using the up-downmethod of Dixon (1980). Testing was started with the 2.04 g hair, in themiddle of the series. Stimuli were always presented in a consecutiveway, whether ascending or descending. In the absence of a paw withdrawalresponse to the initially selected hair, a stronger stimulus waspresented; in the event of paw withdrawal, the next weaker stimulus waschosen. Optimal threshold calculation by this method requires 6responses in the immediate vicinity of the 50% threshold, and countingof these 6 responses began when the first change in response occurred,e.g. the threshold was first crossed. In cases where thresholds felloutside the range of stimuli, values of 15.14 (normal sensitivity) or0.41 (maximally allodynic) were respectively assigned. The resultingpattern of positive and negative responses was tabulated using theconvention, X=no withdrawal; O=withdrawal, and the 50% withdrawalthreshold was interpolated using the formula:50% g threshold=10^((Xf+kδ))/10,000where Xf=value of the last von Frey hair used (log units); k=tabularvalue (from Chaplan et al. (1994)) for the pattern of positive/negativeresponses; and δ=mean difference between stimuli (log units). Hereδ=0.224.

Von Frey thresholds were converted to percent of maximum possible effect(% MPE), according to Chaplan et al. 1994. The following equation wasused to compute % MPE:

${\%\mspace{14mu}{MPE}} = {\frac{\begin{matrix}{{{Drug}\mspace{14mu}{treated}\mspace{14mu}{threshold}\mspace{14mu}(g)} -} \\{{allodynia}\mspace{14mu}{threshold}\mspace{14mu}(g)}\end{matrix}}{\begin{matrix}{{{Control}\mspace{14mu}{threshold}\mspace{14mu}(g)} -} \\{{allodynia}\mspace{14mu}{threshold}\mspace{14mu}(g)}\end{matrix}} \times 100}$Administration of Test Substance

Rats were injected (subcutaneously, intraperitoneally, intravenously ororally) with a test substance prior to von Frey testing, the timebetween administration of test compound and the von Frey test varieddepending upon the nature of the test compound.

Writhing Test

Acetic acid will bring abdominal contractions when administeredintraperitoneally in mice. These will then extend their body in atypical pattern. When analgesic drugs are administered, this describedmovement is less frequently observed and the drug selected as apotential good candidate.

A complete and typical Writhing reflex is considered only when thefollowing elements are present: the animal is not in movement; the lowerback is slightly depressed; the plantar aspect of both paws isobservable. In this assay, compounds of the present inventiondemonstrate significant inhibition of writhing responses after oraldosing of 1–100 μmol/kg.

(i) Solutions Preparation

Acetic acid (AcOH): 120 μL of Acetic Acid is added to 19.88 ml ofdistilled water in order to obtain a final volume of 20 ml with a finalconcentration of 0.6% AcOH. The solution is then mixed (vortex) andready for injection.

Compound (drug): Each compound is prepared and dissolved in the mostsuitable vehicle according to standard procedures.

(ii) Solutions Administration

The compound (drug) is administered orally, intraperitoneally (i.p.),subcutaneously (s.c.) or intravenously (i.v.)) at 10 ml/kg (consideringthe average mice body weight) 20, 30 or 40 minutes (according to theclass of compound and its characteristics) prior to testing. When thecompound is delivered centrally: Intraventricularly (i.c.v.) orintrathecally (i.t.) a volume of 5 μL is administered.

The AcOH is administered intraperitoneally (i.p.) in two sites at 10ml/kg (considering the average mice body weight) immediately prior totesting.

(iii) Testing

The animal (mouse) is observed for a period of 20 minutes and the numberof occasions (Writhing reflex) noted and compiled at the end of theexperiment. Mice are kept in individual “shoe box” cages with contactbedding. A total of 4 mice are usually observed at the same time: onecontrol and three doses of drug.

For the anxiety and anxiety-like indications, efficacy has beenestablished in the geller-seifter conflict test in the rat.

For the functional gastrointestina disorder indication, efficacy can beestablished in the assay described by Coutinho SV et al, in AmericanJournal of Physiology—Gastrointestinal & Liver Physiology.282(2):G307–16, 2002 February, in the rat.

1. A method for the treatment of anxiety, comprising administering to asubject suffering from anxiety an effective amount of a compound of theformula I

wherein R¹ is selected from any one of

wherein each R¹ phenyl and R¹ heteroaromatic ring may optionally andindependently be further substituted by 1, 2 or 3 substituents selectedfrom CF₃, methyl, iodo, bromo, fluoro and chloro; R² is independentlyselected from ethyl and isopropyl; R³ is independently selected fromhydrogen and fluoro; R⁴ is independently selected from —NH₂ and—NHSO₂R⁵; and R⁵ is independently selected from hydrogen, —CF₃ and C₁–C₆alkyl, or salts thereof or separate enantiomers and salts thereof.
 2. Acompound according to claim 1, wherein R¹ is phenyl, pyrrolyl orfuranyl; R² is ethyl or isopropyl; R³ is hydrogen or fluoro; and R⁴ is—NH₂, wherein said phenyl, pyrrolyl, and furanyl are optionallysubstituted with one or more groups selected from CF₃, methyl, iodo,bromo, fluoro, and chloro.
 3. A method according to claim 1, wherein R¹is phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; R² is ethyl orisopropyl; R³ is hydrogen or fluoro; R⁴ is —NH₂ or —NHSO₂R⁵; and R⁵ isC₁–C₆ alkyl.
 4. A method according to claim 1, wherein R¹ is phenyl,pyrrolyl, furanyl, thienyl or imidazolyl; R² is ethyl or isopropyl; R³is hydrogen; R⁴ is —NHSO₂R⁵; and R⁵ is C₁–C₆ alkyl.
 5. A methodaccording to claim 1, wherein the R¹ heteroaromatic ring is substitutedby 1, 2 or 3 substituents selected from CF₃, methyl, iodo, bromo, fluoroor chloro.
 6. A method according to claim 1, wherein the R¹heteroaromatic ring is substituted by 1, 2 or 3 substituents selectedfrom methyl.
 7. A method according to any one of claims 1–6, wherein thesalt of the compound of formula I is a hydrochloride, dihydrochloride,sulfate, tartrate, ditrifluoroacetate, or citrate salt.
 8. A method fortreating anxiety, comprising administering to a subject suffering fromanxiety a pharmaceutical composition comprising a compound of theformula I

wherein R¹ is selected from any one of

wherein each R¹ phenyl and R¹ heteroaromatic ring may optionally andindependently be further substituted by 1, 2 or 3 substituents selectedfrom CF₃, methyl, iodo, bromo, fluoro and chloro; R² is independentlyselected from ethyl and isopropyl; R³ is independently selected fromhydrogen and fluoro; R⁴ is independently selected from —NH₂ and—NHSO₂R⁵; and R⁵ is independently selected from hydrogen, —CF₃ and C₁–C₆alkyl, or salts thereof or separate enantiomers and salts thereof; and apharmacologically and pharmaceutically acceptable carrier.
 9. A methodfor treating anxiety, comprising administering to a subject sufferingfrom anxiety an effective amount of at least one compound selected from:4-[1-(4-Benzyl-piperazin-1-yl)-1-(4-fluoro-3-hydroxy-phenyl)-methyl]N,N-diisopropyl-benzamide;4-[1-(4-Fluoro-3-hydroxy-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin-1-yl)-methyl]-N,N-diisopropyl-benzamide;4-{1-(4-Fluoro-3-hydroxy-phenyl)-1-[4-(1H-imidazol-2-ylmethyl)-piperazin-1-yl]-methyl}-N,N-diisopropyl-benzamide;4-[1-(3-Amino-phenyl)-1-(4-benzyl-piperazin-1-yl)-methyl]-N,N-diisopropyl-benzamide;4-[1-(3-Amino-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin-1-yl)-methyl]-N,N-diisopropyl-benzamide;4-{1-(3-Amino-phenyl)-1-[4-(1H-imidazol-2-ylmethyl)-piperazin-1-yl]-methyl}-N,N-diisopropyl-benzamide;N,N-Diisopropyl-4-[1-(3-methanesulfonylamino-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin-1-yl)-methyl]-benzamide;4-([4-(3-furylmethyl)-1-piperazimyl]{3-[(methylsulfonyl)amino]phenyl}-N,N-diisopropyl-benzamide;4-{(3-aminophenyl)[4-(3-thienylmethyl)-1-piperazinyl]methyl}-N,N-diethylbenzamide;4-[(3-aminophenyl)(4-benzyl-1-piperazinyl)methyl]-N,N-diethylbenzamide;and4-((4-benzyl-1-piperazinyl){3-[(methylsulfonyl)amino]phenyl}methyl)-N,N-diethylbenzamide.